Animal studies with doravirine have failed to reveal evidence of embryofetal toxicity at exposures about 9 times (rats) and 8 times (rabbits) the exposure in humans at the recommended human dose. Animal studies with lamivudine have failed to reveal evidence of teratogenicity at doses producing Cmax about 35 times higher (rats and rabbits) than human exposure at the recommended daily dose; while early embryolethality was observed in rabbit studies (exposure levels similar to human levels), this effect was not seen in high-dose studies in rats. Animal studies with tenofovir disoproxil fumarate (DF) have failed to reveal evidence of fetal harm at doses up to 14 times (rats) and 19 times (rabbits) the human dose based on body surface area. Placental transfer of doravirine to the fetus was observed with fetal plasma levels of up to 40% (rabbits) and 52% (rats) that of maternal levels on gestation day 20; placental transfer of lamivudine and tenofovir DF has been observed in humans. There are no controlled data in human pregnancy with this combination drug.

Placental transfer to the fetus has been reported as high (cord blood/maternal delivery plasma drug ratio greater than 0.6) with lamivudine and tenofovir DF.

In 2 clinical trials, maternal, neonatal, and umbilical cord serum lamivudine levels were generally comparable. Amniotic fluid samples collected after natural rupture of membranes from a subset of patients confirmed placental transfer in humans. Amniotic fluid levels of lamivudine were usually 2 times greater than maternal serum levels, ranging from 1.2 to 2.5 mcg/mL (150 mg twice a day) and 2.1 to 5.2 mcg/mL (300 mg twice a day).

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral therapy, an Antiretroviral Pregnancy Registry (APR) has been established. Healthcare providers are encouraged to prospectively register patients. For additional information: apregistry.com

The APR has received prospective reports of over 12,600 exposures to lamivudine-containing regimens (over 5200 exposed in the first trimester; over 7400 exposed in the second/third trimester) resulting in live births; there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For lamivudine, enough first trimester exposures have been monitored to detect at least a 1.5-fold increased risk of overall birth defects and a 2-fold increase in risk of cardiovascular and genitourinary defects (the more common classes); no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to lamivudine was 3.1% and 2.9%, respectively.

The APR has received prospective reports of over 5700 exposures to tenofovir DF-containing regimens (over 4000 exposed in the first trimester; over 1700 exposed in the second/third trimester) resulting in live births; there was no difference between tenofovir DF and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population. For tenofovir DF, enough first trimester exposures have been monitored to detect at least a 1.5-fold increased risk of overall birth defects and a 2-fold increase in risk of cardiovascular and genitourinary defects (the more common classes); no such increases detected. The prevalence of birth defects with first trimester and second/third trimester exposures to tenofovir DF was 2.4% and 2.4%, respectively.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

According to some authorities: As a precaution, use should be avoided.

US FDA pregnancy category: Not assigned.

Risk summary: No data available on use of this drug in pregnant women to inform a drug-related risk.

Comments:
-A pregnancy exposure registry is available.

See references

LAMIVUDINE AND TENOFOVIR DISOPROXIL FUMARATE (DF):
Lamivudine, tenofovir (doses not provided; presumed 300 mg/day for each component), and efavirenz were administered daily (between 6 and 8 p.m.) for prevention of mother-to-child HIV transmission. At 1 month postpartum, milk samples were collected in the morning from 33 women; lamivudine level was 537 mcg/L (interquartile range [IQR]: 369 to 768 mcg/L) and tenofovir level was 5 mcg/L (IQR: 0 to 6.1 mcg/L). At 12 months postpartum, milk samples were collected in the morning from 47 women; lamivudine level was 430 mcg/L (IQR: 266 to 531 mcg/L) and tenofovir level was 2.5 mcg/L (IQR: 0 to 5.5 mcg/L). Blood samples were obtained from 25 of their breastfed infants; the morning infant plasma level of lamivudine and tenofovir at 6 months of age was 2.5 mcg/L (IQR: 2.5 to 7.6 mcg/L) and 24 mcg/L (IQR: 0 to 51.6 mcg/L), respectively, and was 0 mcg/L (for each component) at 12 months of age.

A study of 136 breastfed infants of mothers who used lamivudine, tenofovir, and efavirenz during pregnancy and postpartum measured bone markers at 1, 6, and 12 months of age; markers included bone-specific alkaline phosphatase and C-terminal telopeptide of type I collagen. Although tenofovir is known to affect bone density and bone mineral density in adults, no effects were seen on infants' bone markers in the study.

LAMIVUDINE:
Based on more than 200 mother/child pairs treated for HIV, serum lamivudine levels in breastfed infants of mothers treated for HIV are very low (less than 4% of maternal serum levels) and gradually decrease to undetectable levels by 24 weeks of age. No data available on the safety of lamivudine when administered to infants younger than 3 months.

Milk samples were obtained daily before breastfeeding. The milk lamivudine level averaged 1.2 mg/L (range: less than 0.5 to 6.1 mg/L) with 300 mg twice a day (n=10) and 0.9 mg/L (range: less than 0.5 to 8.2 mg/L) with 150 mg twice a day plus zidovudine (n=10).

Milk samples from 20 women taking lamivudine 150 mg orally twice a day as part of combination antiretroviral therapy (cART) and serum levels from their infants were obtained at 2 or 5 months postpartum, about 4 hours (range: 1 to 8.5 hours) after the last dose. The lamivudine level in breast milk averaged 1.8 mg/L and the infant serum lamivudine level averaged 28 mcg/L (range: less than 14 to 53 mcg/L).

Blood and milk samples were obtained from 40 women on postpartum prophylaxis (with lamivudine, nevirapine, and [zidovudine or stavudine]; doses not provided) once during the first 3 days postpartum and once at 7 days postpartum. Samples were collected after a dose at 5.3 hours (range: 0 to 99 hours) for the first sample and 6 hours (range: 4.3 to 20 hours) for the second sample. Breast milk lamivudine levels averaged 0.4 mg/L (n=9) for the first sample and 0.4 mg/L (n=30) for the second sample; these levels were 2.9 to 3.3 times the coinciding maternal serum levels.

Mothers using lamivudine (dose not provided) as part of cART provided 47 breast milk and serum samples at 6, 12, and 24 weeks postpartum. The breast milk lamivudine levels at about 14 hours after the last dose averaged 510 (17 samples), 387 (17 samples), and 310 mcg/L (13 samples). Milk levels were about 2.6 times (IQR: 1.1 to 3.5 times) the maternal plasma levels; lamivudine milk to plasma ratio was 2.96 in 49 patients in a related study (same authors). Infant serum lamivudine levels measured about 14 hours after the last maternal dose averaged 13, 10, and 5 mcg/L at 6 (17 samples), 12 (17 samples), and 24 (13 samples) weeks of age, respectively, which was 6% of the maternal serum level.

Serum and breast milk from 58 mothers using lamivudine 150 mg twice a day (with nevirapine and zidovudine) and serum levels from their 58 infants were analyzed. Mothers started lamivudine at 34 to 36 weeks gestation and continued until 6 months postpartum; they were instructed to exclusively breastfeed for 5.5 months. Breast milk and serum samples were collected within 24 hours after delivery and at 2, 6, 14, and 24 weeks postpartum; breast milk was collected at various times after the prior dose. The breast milk lamivudine level averaged 1214 mcg/L (all visits). The infant dried blood spot lamivudine levels averaged 67 mcg/L at delivery, 32 mcg/L at week 2, 24 mcg/L at week 6, 20 mcg/L at week 14, and were not measurable (less than 16 mcg/L) at week 24 postpartum. According to author estimation, a fully breastfed infant would receive 182 mcg/kg/day of lamivudine.

A total of 206 milk samples were obtained at birth, 1, 3, and/or 6 months postpartum from 66 mothers using lamivudine 150 mg twice a day as part of cART and 64 blood samples from their breastfed infants were analyzed at 1, 3, and/or 6 months postpartum; samples were collected at about 4.5 hours (range: 3.5 to 6 hours) after the prior maternal dose and about 30 minutes (range: 20 to 60 minutes) after nursing. The breast milk lamivudine level averaged 446 mcg/L (range: 269 to 683 mcg/L). The infant plasma lamivudine level averaged 18 mcg/L (range: 7 to 35 mcg/L), which averaged 2% (range: 0 to 4%) of the maternal serum level. In a continuation of this study, 65 breast milk samples (after the same dose at 1, 3, and 6 months postpartum) and 22 blood samples (from 17 breastfed infants [extent not provided] between 1 and 6 months) were collected for lamivudine analysis; lamivudine levels averaged 684 mcg/L in breast milk and 29.2 mcg/L in infant blood. Not clear if some of the same patients from the first study were in the latter study.

Samples of breast milk were obtained right before a dose at about 1 month postpartum from 15 women using lamivudine 150 mg twice a day for 53 to 182 days as part of cART. Whole breast milk levels contained about 0.14 mg/L of lamivudine (about 74% of maternal blood levels). Infant blood was obtained from 24 infants partially or exclusively breastfed by their mothers at about 1 month postpartum, 11 to 18 hours after the last maternal dose and about 1 hour (range: 6 minutes to 35 hours) after the last breastfeeding. Plasma lamivudine levels were undetectable (less than 7 mcg/L) in all infant samples.

Mothers (n=30) starting lamivudine 150 mg orally twice a day (with zidovudine and lopinavir-ritonavir) at delivery provided plasma and breast milk samples at 6, 12, or 24 weeks postpartum (n=10 each time). Maternal plasma and breast milk samples were collected about 14.9 hours after the prior evening dose, before the morning dose, and 2, 4, and 6 hours after the dose. Infant plasma samples were collected before the first maternal dose and at 2, 4, and 6 hours after the maternal dose. Breastfeeding was not restricted during the study. Detectable lamivudine levels (at least 10 mcg/L) were found in 107 of 121 breast milk samples and 107 of 115 infant plasma samples; breast milk level averaged 0.94 mg/L over the 6 hours and infant plasma level averaged 180 mcg/L.

In 6 HIV-infected breastfeeding mothers using lamivudine 150 mg twice a day, a peak breast milk level of 994 mcg/L (range: 958 to 1274 mcg/L) was reached at 2 to 4 hours after dosing; 2 of their breastfed infants had detectable lamivudine serum levels (13.2 and 15.6 mcg/L).

Nigerian and Ugandan women (n=39) used lamivudine 150 mg twice a day (n=11) or 300 mg once a day (n=10 [morning]; n=18 [prior evening]) as part of combination HIV therapy. Expressed milk samples were collected before dosing and at 0.5, 1, 2, 4, and 8 hours after the morning dose (150 or 300 mg) or between 12 to 20 hours after the evening dose (300 mg). Using dried breast milk spots, peak breast milk level averaged 908 mcg/L (IQR: 772 to 1015 mcg/L) at about 6 hours (IQR: 4 to 6 hours) after dosing and 663 mcg/L (IQR: 445 to 890 mcg/L) at about 6 hours (IQR: 4 to 8 hours) after dosing in mothers using 150 mg twice a day and 300 mg once a day, respectively. Their exclusively breastfed infants were fed on demand and had blood samples collected at 2 and 8 hours after maternal dosing. Lamivudine was detectable (greater than 16.6 mcg/L) in dried blood spots of 14 of 39 infants (averaged 17.7 mcg/L [IQR: 16.3 to 22.7 mcg/L]); of these, levels were detectable in 7 of 10 infants whose mothers used 300 mg once a day in the morning, in 4 of 18 infants whose mothers had used their dose the prior evening, and in 3 of 11 infants whose mothers used 150 mg twice a day.

At 3-hour intervals before cesarean section, 9 HIV-infected women received 3 doses of lamivudine 50 mg, lopinavir 200 mg, ritonavir 150 mg, zidovudine 300 mg. Breast milk samples were obtained at 25 hours postpartum (mean); milk level of lamivudine averaged 449 mcg/L (range: 143 to 1148 mcg/L) in the 8 women it was quantified.

Of 24 infants breastfed by HIV-infected mothers who developed HIV infection by 6 months of age, 6 infants had a mutation that may have been selected for by subtherapeutic levels of lamivudine in breast milk.

An HIV-infected mother used a combination tablet (containing abacavir 600 mg, dolutegravir 50 mg, lamivudine 300 mg) once a day. She exclusively breastfed her infant for about 30 weeks and then partially breastfed for about 20 weeks; no obvious side effects were observed.

TENOFOVIR DF:
Bioavailability of tenofovir is very poor; it is available as tenofovir DF (more bioavailable), which is metabolized intracellularly to tenofovir diphosphate (active metabolite). Although unknown, the bioavailabilities of tenofovir and tenofovir diphosphate from breast milk are believed to be very low.

Data on use of this drug during breastfeeding in HIV-infected mothers and mothers without HIV infection treated for HIV prophylaxis or hepatitis B infection show infant exposure to the drug is trivial. A few infants have been breastfed during maternal use of tenofovir and no side effects have been observed up to 2 years of age.

Samples of breast milk obtained from 5 HIV-1-infected mothers show that tenofovir is secreted in human milk. Average peak and trough drug levels in breast milk were 14.1 and 6.8 mcg/L, respectively. According to author estimation, an exclusively breastfed infant would receive about 0.03% of the proposed dose for infants and attain trivial infant serum levels that would likely have no adverse outcomes.

In a multicenter study, a single 600 or 900 mg dose of tenofovir was administered to mothers during labor; samples of breast milk were collected at various times postpartum. In 75% of samples obtained from 25 mothers during the first 2 days postpartum, tenofovir was detected (greater than 2.5 mcg/L); levels ranged from 6.3 to 17.8 mcg/L. Only 1 of 21 milk samples had detectable tenofovir level (15.7 mcg/L) at 4 to 6 days postpartum.

Preexposure prophylaxis, using emtricitabine 200 mg-tenofovir DF 300 mg daily, was administered by directly observed therapy for 10 days to 50 women without HIV infection who were breastfeeding their infants. On days 7 and 10 of therapy, peak and trough milk samples were collected 1 to 2 hours after dosing and 23 to 24 hours after the previous dose, respectively; a single infant blood sample was collected after the mother's 7th dose. Median peak and trough milk tenofovir levels were 3.2 and 3.3 mcg/L, respectively; these levels correspond to a daily dose of 0.47 to 0.49 mcg/kg (estimated), which is less than 0.01% of the proposed therapeutic dose for infants. Of 49 infant blood samples collected, 46 had undetectable (less than 0.31 mcg/L) tenofovir levels; the 3 detectable tenofovir levels were 0.9, 0.9, and 17.4 mcg/L. Diarrhea lasting 2 to 3 days was reported in 2 of the 50 breastfed infants; no other side effects were reported.

Tenofovir 300 mg/day was administered to 6 HIV-infected breastfeeding mothers; it was measured after dosing during ongoing therapy. Peak breast milk tenofovir level of 5.9 mcg/L (range: 5.5 to 8 mcg/L) was reached at about 3 hours (range: 1 to 7 hours) after dosing; none of the breastfed infants had detectable tenofovir serum levels.

Nigerian and Ugandan women (n=48) used tenofovir DF 300 mg once a day (either in the morning or evening) as part of combination HIV therapy. Expressed milk samples were collected before dosing and several times during the 12 hours after the morning dose (n=30) or at 12, 16, and 20 hours after the prior evening dose (n=18). Using dried breast milk spots, peak breast milk level averaged 5.98 mcg/L (IQR: 0 to 8.05 mcg/L) at about 4 hours (IQR: 1 to 6 hours) after dosing. Their exclusively breastfed infants were fed on demand and had blood samples collected at 2 and 8 hours after maternal dosing; no infants had measurable (greater than 4.2 mcg/L) tenofovir blood level in dried blood spots.

Serum tenofovir levels were measured in 5 infants exclusively breastfed by 4 mothers using tenofovir 245 mg (presumably tenofovir DF 300 mg) daily; infant age averaged 1.8 months. In 4 infants, serum tenofovir was undetectable (less than 0.005 mg/L); in 1 infant, serum tenofovir was 0.0055 mg/L. At 4 months of age, no adverse outcomes (on standard developmental parameters) were observed in 2 of the infants exclusively breastfed for 3 months.

In a study of women and their infants using antiretroviral therapy for HIV infection, mothers who used a tenofovir-containing regimen were compared to those who did not. The risk of infant death decreased by 57% in infants breastfed and exposed to tenofovir compared to infants who were not breastfed; no alterations in growth and development were observed in breastfed infants during 2 years of follow-up.

A prospective cohort study compared growth and development of infants of non-HIV-infected mothers and infants of HIV-infected mothers using tenofovir and efavirenz as part of combination HIV therapy; infants were followed up to 12 months of age. No differences in the groups were found in any growth parameters.

Breastfeeding is not recommended during use of this drug; if replacement feeding is not an option, a different drug may be preferred.

Excreted into human milk: Unknown (doravirine); Yes (lamivudine, tenofovir)
Excreted into animal milk: Yes (doravirine)

Comments:
-The effects in the nursing infant are unknown; potential for HIV-infected infants developing viral resistance and breastfed infants developing side effects
-The US CDC, American Academy of Pediatrics, and manufacturer advise HIV-infected women not to breastfeed to avoid postnatal transmission of HIV to a child who may not yet be infected.
-Local guidelines should be consulted if replacement feeding is not an option.

See references